1. Field of the Invention
Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides two enantioselective synthetic routes to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu®, as well as novel phosphonate compounds, via D-xylose or bromobenzene.
2. Background
Influenza remains a major health problem for humans and animals. (Kaye and Pringle, Clin. Infect. Dis. 2005, 40, 108; and Beigel et al., N. Engl. J. Med. 2005, 353, 1374) At present, four drugs are approved for influenza prophylaxis and treatment: amantadine and rimantadine act as the M2 ion channel Mockers, whereas Tamiflu® (the phosphate salt of oseltamivir ethyl ester, Roche Laboratories, Inc.) and Relenza™ (zanamivir, GlaxoWellcome, Inc.) inhibit the activity of neuraminidase (NA). (Moscona, A. N. Engl. J. Med. 2005, 353, 1363; Ward et al., J. Antimicrob. Chemother. 2005, 55, Suppl. S1, i5; and De Clercq, E. Nature Rev. Drug Discov. 2006, 5, 1015.) Recent reports on the drug resistant avian flu infections and the side effects in children receiving Tamiflu® treatments suggest that new chemical identities for neuraminidase inhibitors are needed for the battle against the threat of the pandemic flu. Before a safe and effective vaccine is available to protect the possible pandemic avian flu, neuraminidase inhibitors are one of the few therapeutic approaches available.
The NA inhibitors (NAIs) are designed to have (oxa)cyclohexene scaffolds to mimic the oxonium transition-state in the enzymatic cleavage of sialic acid. (von Itzstein, M. et al. Nature 1993, 363, 418; Lew et al., Curr. Med. Chem. 2000, 7, 663; and Russell et al., Nature 2006, 443, 45). Tamiflu® (i, shown in Scheme 1) is an orally administrated anti-influenza drug. (Kim et al., J. Am. Chem. Soc. 1997, 119, 681; Rohloff et al., J. Org. Chem. 1998, 63, 4545; Karpf and Trussardi, J. Org. Chem. 2001, 66, 2044; Harrington et al., Org. Process Res. Dev. 2004, 8, 86; Yeung et al., J. Am. Chem. Soc. 2006, 128, 6310; Fukuta et al., J. Am. Chem. Soc. 2006, 128, 6312; Farina and Brown, Angew. Chem. Int. Ed. 2006, 45, 7330; Mita et al., Org. Lett. 2007, 9, 259; Yamatsugu et al., Tetrahedron Lett. 2007, 48, 1403) On hydrolysis by hepatic esterases, the active carboxylate, oseltamivir (2, also known as GS4071), is exposed to interact with three arginine residues (Arg118, Arg292 and Arg371) in the active site of NA. (von Itzstein, et al., 1993; Lew et al., 2000, and Russell et al., 2006).
The phosphonate group is generally used as a bioisostere of carboxylate in drug design. (White et al., J. Mol. Biol. 1995, 245, 623; Streicher et al., Tetrahedron 2001, 57, 8851; Streicher, Bioorg. Med. Chem. Lett. 2004, 14, 361; Schug and Lindner, W. Chem. Rev. 2005, 105, 67; Streicher and Busseb, Bioorg. Med. Chem. 2006, 14, 1047). Preliminary molecular docking experiments (FIG. 1) using the known N1 crystal structure (PDB code: 2HU4) (Russell et al., 2006) reveal that the putative phosphonate inhibitor 3a binds strongly with the tri-arginine residues of NA, in addition to other interactions exerted by the C3-pentyloxy, C4-acetamido and C5-amino groups in the binding pocket similar to the NA-oseltamivir complex. In comparison with the carboxylate-guanidinium ion pair, a phosphonate ion exhibits stronger electrostatic interactions with the guanidinium ion. Previously reported methods (including, e.g., Bischofberger et al., U.S. Pat. No. 5,763,483, incorporated herein by reference) for the synthesis of oseltamivir/Tamiflu are not amenable to exchange of the C-1 carboxyl group to a phosphonate group; therefore, a novel approach to the synthesis of both known and novel neuraminidase inhibitors is desirable.